The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions

  • Eur J Med Chem. 2020 Mar 1;189:112042. doi: 10.1016/j.ejmech.2020.112042.
Han Wu  1 ,  Yu Sun  2 ,  Wee Lin Wong  3 ,  Jiajia Cui  4 ,  Jingyang Li  5 ,  Xuefu You  2 ,  Lee Fah Yap  3 ,  Yu Huang  1 ,  Wei Hong  6 ,  Xinyi Yang  7 ,  Ian C Paterson  8 ,  Hao Wang  9
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
  • 2. Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 3. Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala, Lumpur, Malaysia.
  • 4. Department of Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, 710100, China.
  • 5. Department of Pharmacy, Logistics University of Chinese People's Armed Police Forces, Tianjin, 300309, China.
  • 6. School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan, 750021, China; Key Laboratory of Chemical Engineering and Technology, State Ethnic Affairs Commission, North Minzu University, Yinchuan, 750021, China. Electronic address: [email protected].
  • 7. Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 8. Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala, Lumpur, Malaysia. Electronic address: [email protected].
  • 9. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; School of Pharmacy, Minzu University of China, Beijing, 100081, China; Key Laboratory of Ethnomedicine (MINZU University of China), Ministry of Education, Beijing, 100081, China. Electronic address: [email protected].
PMID: 31958737 DOI: 10.1016/j.ejmech.2020.112042
Abstract

Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and Cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β Receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β Receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists.

Keywords
Epithelial to mesenchymal transition; Protein-protein interactions; TGF-β inhibitor; Transforming growth factor-β inhibitor.
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